Advanced KRAS mutation-positive non-small-cell lung cancer patients do not benefit from a second-line combination of selumetinib and docetaxel

medwireNews: Adding selumetinib to docetaxel
does not improve progression-free survival (PFS) in patients who have previously been treated for advanced KRAS-mutated non-small-cell lung cancer (NSCLC), report the SELECT-1 investigators.

The primary endpoint of median PFS was 3.9 months for the 254 patients who were randomly assigned to receive a continuous 75 mg twice daily dose of the oral MEK1/2 inhibitor alongside docetaxel 75 mg/m2 given on day 1 of a 21-day cycle.

This did not significantly differ from the 2.8 months achieved by the 254 patients given placebo plus docetaxel, write Pasi Jänne, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in JAMA.

Median overall survival was also comparable in the selumetinib–docetaxel and placebo–docetaxel groups, at 8.7 versus 7.9 months. Although the selumetinib regimen led to a significantly higher objective response rate (ORR; 20.1 vs 13.7%, odds ratio=1.61), median duration of response was similar between the arms (2.9 vs 4.5 months).

Patients in the selumetinib–docetaxel group, compared with those given placebo–docetaxel, experienced higher rates of grade 3 or more serious side effects (67 vs 45%), serious adverse events (49 vs 32%), and adverse events leading to hospitalisation (46 vs 30%).

Dose reductions were also more common in the selumetinib–docetaxel group, affecting 28% of patients versus 6% of those given placebo, as were treatment interruptions (41 vs 21%) and discontinuation of the study treatment (23 vs 9%) and docetaxel (29 vs 15%).

The researchers note that placebo–docetaxel had greater efficacy in the current study than the earlier phase II trial, while the selumetinib–docetaxel regimen had poorer efficacy.

Hypothesizing that differences in the distribution of KRAS mutation subtypes between the phase II and III trials could partially account for this, the team compared findings for 301 SELECT-1 participants with a KRAS G12C or G12CV mutation and 195 patients with other KRAS variants.

However, PFS did not significantly correlate with mutation group or individual KRAS mutation. And while the ORR was higher in patients with a KRAS G12C or G12C mutation who were assigned to receive the selumetinib regimen compared with those given placebo–docetaxel, the researchers say that “this was not translated into a meaningful [PFS] benefit.”

Jacob Kaufman, from Duke University, and Thomas Stinchcombe, from the Duke Cancer Institute, both based in Durham, North Carolina, USA, question in an accompanying comment whether other mutations associated with response to MEK inhibition, such as concurrent loss of the LKB1 tumour suppressor gene, may also have influenced the trial results.

They suggest it may be “premature” to rule out other MEK inhibitors in KRAS-mutated NSCLC and that other chemotherapy agents in combination with MEK inhibitors “may have more synergy than was observed with docetaxel.”

The commentators conclude: “The next generation of targeted therapies will likely focus on the primary oncogenic molecular event and the acquired resistance mechanisms, and will be more potent and specific for the oncogenic driver.

“This will ideally improve efficacy and reduce off-target toxicities,” they write, adding: “The development of a targeted therapy is critical to the future management of patients with KRAS-mutant NSCLC and may provide a path forward for other solid tumor malignancies that harbor KRAS mutations.”